NK1 receptor antagonist blocks angiotensin II responses in renin transgenic rat medulla oblongata.
Angiotensin (Ang) II increases substance P (SP) efflux from perfused slices of medulla oblongata, and a peptide antagonist of SP, [Leu11,psiCH2NH10-11]SP, blocks the acute hypotension and bradycardia caused by Ang II injected into the nucleus tractus solitarii (nTS) of Harlan Sprague-Dawley (SD) rats. We investigated whether the same relationships exist in (mRen2)27 renin transgenic (TG) rats, which have chronic elevations of medullary tissue Ang II levels. Ang II increased SP efflux (48% above control; P<0.01) from slices of medulla prepared from 8- to 12-week old male TG rats. Injections of Ang II (250 fmol in 30 nL) into the nTS of chloralose-urethane anesthetized TG rats produced a significant increase in pressure of 7+/-2 mm Hg before a 13+/-3 mm Hg fall in pressure. Ang II induced similar depressor responses in Hannover SD rats but no increase in pressure. After nTS injection of the NK1-selective SP antagonist CP-96,345 (30 pmol in 60 nL), Ang II-induced hypotension was blocked in both groups, as was the pressor component in hypertensive rats. Hypotensive and bradycardic effects of glutamate (0.6 nmol in 30 nL) injected into the nTS were not altered by CP-96,345. In vitro receptor autoradiography showed that the SP antagonist (10 or 100 microM) did not compete for 125I-Ang II binding in the dorsal medulla, a result suggesting that it did not interact directly with Ang II receptors. Thus, the nTS cardiovascular effects of Ang II are mediated by SP in both normotensive rats and a model of hypertension with altered endogenous levels of Ang II. These findings link Ang II-induced effects on SP release from brain slices of the medulla oblongata to acute cardiovascular actions of the peptide through an NK1 receptor.
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Hypertension Center, Division of Surgery, Wake Forest University, Winston-Salem, NC 27157-1032, USA.
Westwood
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Bosch
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Ganten
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Ferrario
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C
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology*; D064729:Neurokinin-1 Receptor Antagonists; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000032:analysis / Q000378:metabolism; D012083:Renin / Q000096:biosynthesis* / Q000235:genetics; D017552:Solitary Nucleus / Q000187:drug effects / Q000502:physiology; D013373:Substance P / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D013599:Systole / Q000187:drug effects
D001713:Biphenyl Compounds; D064729:Neurokinin-1 Receptor Antagonists; D011945:Receptors, Angiotensin; C107563:substance P, Leu(11),CH2NH-(10-11)-; D000804:Angiotensin II; D013373:Substance P; D012083:Renin; C066892:CP 96345